tbuckley/cabot-search huggingface dataset:
Abstract 5157: ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer
Authors: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Michael Oh, Camelia Dumitras, Nico Edgar, Ryan Chew, Rashel Jacobo, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Steven Dubinett, Bin Liu
Journal: Cancer Research (2023)

Abstract Lung cancer remains the deadliest form of cancer, claiming the lives of 1.8 million individuals worldwide in 2020. While treatment options have improved with the advent of immune checkpoint inhibitors (ICI), many patients do not respond to immunotherapy or develop resistance following initial response. A significant subset of non-small cell lung cancer (NSCLC) patients harbor somatic co-mutations in Kirsten rat sarcoma virus (KRAS) and Liver kinase 1 [LKB1, also known as serine/threonine kinase 11 (STK11)] genes, whose tumors are characterized by a predominance of neutrophils and an immune suppressive tumor microenvironment (TME) that are resistant to ICI. Our studies revealed that all-trans retinoic acid (ATRA), a metabolite derived from vitamin A, sensitized a murine model of NSCLC (Kras G12D P53−/−Lkb1−/−; KPL) to PD-1 blockade. The ATRA and anti-PD-1 combination therapy improved local and systemic T cell activation and generated systemic tumor-specific immunity. We further observed that ATRA augmented anti-PD-1 efficacy in additional murine NSCLC models with or without LKB1 loss. To understand ATRA-mediated anti-tumor effects, we performed single cell RNA sequencing (scRNA-seq) of KPL murine tumors with or without 6 daily ATRA treatments. scRNA-seq analysis indicated a reduction of neutrophils as well as an enrichment in T cell and natural killer (NK) cell populations in the TME. Furthermore, scRNA-seq analysis revealed elevated expression of interferon (IFN) downstream genes in multiple immune subpopulations in the TME. Preliminary ex vivo studies indicated that ATRA increases NOX2 levels, intracellular reactive oxygen species (ROS), and IFN signaling in the myeloid-derived suppressor cells (MDSC) of KPL tumors. Our findings suggest that ATRA may reshape the TME by activating IFN signaling in multiple cell subtypes to sensitize resistant tumors to ICI immunotherapy. Citation Format: William P. Crosson, Rui Li, Ramin Salehi-Rad, Raymond J. Lim, Jensen Abascal, Bitta P. Kahangi, Edgar Perez Reyes, Michael Oh, Camelia Dumitras, Nico Edgar, Ryan Chew, Rashel Jacobo, Zhe Jing, Kostyantyn Krysan, Linh M. Tran, Steven Dubinett, Bin Liu. ATRA treatment induces an interferon response to reprogram the immunosuppressive tumor microenvironment and overcomes resistance to immune checkpoint inhibition in murine models of LKB1 deficient non small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5157.
Abstract 2179: The role of ATP-binding cassette transporter A5 in colorectal cancer progression
Authors: Khuloud Bajbouj, Latifah Alketbi, Qutayba Hamid, Iman Talaat
Journal: Cancer Research (2023)

Abstract Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, several ABCA superfamily transporters have been shown to mediate cancer development and multidrug resistance. However, the role of ABCA5 in CRC development and progression is elusive. The current study aimed at profiling the expression of ABCA5 at the different grades of CRC. Experimental Methods: Forty-nine (9 Well differentiated, 26 moderately differentiated and 14 poorly differentiated) primarily diagnosed CRC cases, and 15 normal colonic tissues were included in the study. Formalin-fixed paraffin-embedded samples were interpreted for the differential expression of ABCA5 by immunohistochemistry. The immunoreactivity of ABCA5 was assessed in the cells based on the staining intensity and the percentage of the positively stained cells to create the immunoreactive score. Results: In total, 49 CRC cases were recruited, with a mean age of 63.77 years (range 33-86); 21 female and 28 male patients. All specimens were diagnosed as adenocarcinoma (NOS). Immunohistochemical analysis of the 49 CRC samples revealed diffuse ABCA5 immunoreactivity in the majority of cases. Seven cases showed mild expression, 25 showed moderate expression, whereas 17 cases revealed intense ABCA5 expression. Intriguingly, negative to a mild expression of ABCA5 was noted in the normal colonic tissues. ABCA5 intensity was higher in poorly differentiated CRC compared to the other grades. Conclusion: Higher expression of ABCA5 is associated with CRC differentiation, indicating that it might contribute to CRC development and progression. Thus, it may be a novel diagnostic biomarker. Citation Format: Khuloud Bajbouj, Latifah Alketbi, Qutayba Hamid, Iman Talaat. The role of ATP-binding cassette transporter A5 in colorectal cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2179.
Abstract 25: MIF and NR3C2 interactively regulate glucose metabolism in pancreatic cancer
Authors: Shouhui Yang, Wei Tang, Azadeh Azizian, Philipp Ströbel, Yuuki Ohara, Helen Cawley, Nader Hanna, B. Michael Ghadimi, Nagireddy Putluri, S. Perwez Hussain
Journal: Cancer Research (2023)

Abstract Inflammation and altered cellular metabolism are described as hallmarks of cancer. Although inflammatory signaling and metabolic reprogramming are highly integrated and play critical role in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The role of inflammatory mediators in the regulation of metabolic reprogramming is not adequately studied in pancreatic cancer and remains to be explored. Here we show that macrophage migration inhibitory factor (MIF) collaborates with its downstream transcriptional factor nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2) regulate metabolic reprogramming to support cancer growth and progression in PDAC. MIF enhances glucose uptake and lactate efflux through enhancing HK1 (hexokinase 1), HK2 (hexokinase 2) and LDHA (lactate dehydrogenase) expression in pancreatic cancer cell in vitro and in an orthotopic mouse model. Furthermore, a decreased HK1, HK2, LDHA expression, pyruvate and lactate production are found in patient tumors with lower MIF expression and MIF-deficiency tumors from genetically engineered KPC mouse model. Conversely, NR3C2 suppresses HK1, HK2, and LDHA expression and decreases glucose uptake and lactate efflux in pancreatic cancer. Mechanistically, MIF-mediated regulation of glycolytic metabolism involves MAPK-ERK Kinase pathway while NR3C2 interacts with AP-1 transcriptional factor in regulation of glycolysis metabolism. Taken together, our result demonstrates an interactive role of MIF and NR3C2 signaling in regulation cancer metabolism and therapeutic approaches target this axis may improve disease outcome in patients with PDAC. Citation Format: Shouhui Yang, Wei Tang, Azadeh Azizian, Philipp Ströbel, Yuuki Ohara, Helen Cawley, Nader Hanna, B. Michael Ghadimi, Nagireddy Putluri, S. Perwez Hussain. MIF and NR3C2 interactively regulate glucose metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 25.
Abstract 998: A blood-based extracellular vesicles DNA methylation signature for colorectal cancer screening
Authors: Sheng Zhang, Faming Wang, Mingxi Chen, Jeongyun Kim, Mengrou Lu, Hongzhang He, Siyang Zheng
Journal: Cancer Research (2023)

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer related deaths, accounting for an estimated 1.8 million new cancer diagnoses and over 880,000 deaths in 2018. Furthermore, CRC patients who are diagnosed at the most advanced (metastatic) stage is estimated to have the 5-year survival rate of 14%. Dramatically, studies shows that if it can be detected at an early stage when surgical removal is feasible, the 5-year survival rate significantly increases to 90%. Therefore, early detection for CRC with curative treatment intent is crucially important to significantly reduce the mortality and morbidity and even cure CRC. Extracellular vesicles (EVs) are lipid-bilayer-enclosed vesicles of sub-micrometer size that are secreted by virtually all cell types. They contain hundreds of different proteins, thousands of intact RNA species, and double-stranded DNA (dsDNA) fragments that sample the entire human genome. Recent findings further corroborate the potential role of EVs in early cancer screening, cancer diagnosis, treatment selection and monitoring. In this study, we used lipid nanoprobe (LNP) for EV isolation and methylation-specific qPCR assay for detecting SEPT9 methylation to develop a minimal invasive CRC screening test. Firstly, we have successfully detected promoter methylation of cancer specific genes SEPT9 in EVs derived from both genomic DNA and EV DNA of the CRC cell line. Secondly, we isolated EV using LNP from plasma samples in a cohort of 19 CRC patients and 9 healthy donor controls. In parallel, we isolated circulating free DNA (cfDNA) from the same cohort of the plasma samples using commercially cfDNA isolation Kit. Then, SEPT9 methylation signature was analyzed by our quantitative real-time PCR assay in these 28 EV DNA samples and 28 cfDNA samples, respectively. In the 19 CRC samples, we identified 10 SEPT9 gene methylation samples from LNP-isolated EV DNA and cfDNA, respectively. In 9 healthy control samples, no SEPT9 methylation was detection in the EV-DNA samples, while one false-positive was detected with cfDNA. Thus, the sensitivity and specificity of EV-DNA in the detection of SEPT9 gene methylation from CRC were determined to be 53% and 100% respectively. In comparison, the sensitivity and specificity of cfDNA are 53% and 89%, respectively from this preliminary pilot study. This indicated that EV-DNA might be superior to cfDNA in detecting SEPT9 gene methylation for CRC screening. Citation Format: Sheng Zhang, Faming Wang, Mingxi Chen, Jeongyun Kim, Mengrou Lu, Hongzhang He, Siyang Zheng. A blood-based extracellular vesicles DNA methylation signature for colorectal cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 998.
Abstract 956: <i>FBXW7</i> regulates imatinib chemoresistance through targeting <i>MCL1</i> for apoptotic regulation in gastrointestinal stromal tumors
Authors: Xiyu Wu, Masaaki Iwatsuki, Meiyue Lou, Takatsugu Ishimoto, Yoshifumi Baba, Yuji Miyamoto, Hideo Baba
Journal: Cancer Research (2023)

Abstract Introduction: Imatinib definitively contribute to improve prognosis for high-risk or unresectable GISTs. Due to therapeutic efficacy is limited by imatinib chemoresistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that early enable patients to utilize more effective therapeutic strategies remains urgent. Here, we evaluate that the ability of FBXW7 acts as a predictor of imatinib therapeutic effect in preclinical models, and the potential of FBXW7-MCL1 axis promote imatinib-induced apoptosis response. Methods: The cellular and in vivo correlation between FBXW7 and imatinib chemoresistance via FBXW7-MCL1 axis were evaluated by detecting IC50 value, apoptosis assay, and GIST xenograft studies. The clinical significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs by immunohistochemical staining and multivariate analyses. Results: FBXW7 affects imatinib chemoresistance through regulating cellular apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate cellular apoptosis. MCL1 involves in the regulation of imatinib chemoresistance through inhibiting apoptosis of GIST-T1 cells. FBXW7 regulates imatinib chemoresistance via down-regulating MCL1 for enhancing imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells via targeting MCL1 to predict therapeutic efficacy of imatinib treatment in vivo. Through 5-year RFS rates analysis and multivariate analysis, the ability of FBXW7 predicting therapeutic efficacy of high-risk GIST patients with adjuvant imatinib was proved. Conclusions: FBXW7 regulates imatinib chemoresistance through inhibiting MCL1 for enhancing imatinib-induced apoptosis in GIST and acted as a reliable predictor of imatinib treatment efficacy in high-risk GIST patients treated imatinib. Citation Format: Xiyu Wu, Masaaki Iwatsuki, Meiyue Lou, Takatsugu Ishimoto, Yoshifumi Baba, Yuji Miyamoto, Hideo Baba. FBXW7 regulates imatinib chemoresistance through targeting MCL1 for apoptotic regulation in gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 956.
Abstract 4086: Mitigating the CD5 CAR-CD5 interaction enhances the functionality of CD5 CAR-T cells by alleviating the T-cell fratricide
Authors: Lee Young Ho, Seung Rok Yu, Jeong Hoon Jeong, Hyeong Ji Lee, Hyeon Jeong Cho, Hyung Cheol Kim
Journal: Cancer Research (2023)

Abstract Chimeric antigen receptor (CAR) T-cell therapy has been used with unprecedented clinical responses in relapsed/refractory B-ALL or B-NHL, MM patients. However, CAR-T therapy has not yet been proven effective in other hematological malignancies, such as T cell lymphoma and leukemia (T-NHL/T-ALL) and acute myeloid leukemia (AML). Developing CAR-T cells for patients with T-cell malignancies remains challenging as most CARs targeting T-lineage antigens, such as CD5, CD7, and CD3, target themselves, potentially resulting in fratricide of CAR-T cells. Thus, there is a need for technical approaches to alleviate the fratricide of CAR-T to treat T-cell malignancies successfully. As part of the approach, we studied whether the affinity of CAR and cognate antigen expression of CAR-T cells influence the intensity of CAR-T`s fratricide and hypothesized that if a single chain Fragment variable (scFv) with a low intensity of fratricide is applied to T-lineage antigen-downregulated CAR-T cells, the effector function of CAR-T cell targeting T cell antigen can be maximized. For this, we screened full human scFvs targeting CD5, a pan T-cell marker, tested the affinity of scFvs for CD5 antigen, and generated anti-CD5 CAR-T cells (CAR5). We evaluated the intensity of in vitro fratricide in CAR5 based on cell expansion and cytokine secretion in vitro and tested their anti-tumor activity in a CD5+ T-ALL xenograft model (Jurkat). In addition, to minimize CAR recognition to a cognate antigen expressed in CAR-T cells, we also generated CD5-downregulated CAR5s (CD5-KD CAR5) using a short hairpin RNA cassette integrated into an anti-CD5 CAR vector to test if the downregulation of CD5 in CAR5s can reduce the fratricide. We found that a CAR5 clone (C7CAR5) with the lowest level of fratricide in vitro, showed superior anti-tumor activity compared to other CAR5s in vivo and that CD5-downregulated C7 CAR5 (CD5-KD C7CAR5) further reduced the fratricide, maximizing the anti-tumor activity. In conclusion, we demonstrate that high-affinity CAR may not always show superior functionality in T cell malignancy CAR-T therapy, explaining one or more strategies to alleviate the fratricide are required. These studies provide the foundation for developing CD5 CART products to treat relapsed T-cell malignancies. Citation Format: Lee Young Ho, Seung Rok Yu, Jeong Hoon Jeong, Hyeong Ji Lee, Hyeon Jeong Cho, Hyung Cheol Kim. Mitigating the CD5 CAR-CD5 interaction enhances the functionality of CD5 CAR-T cells by alleviating the T-cell fratricide. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4086.
Abstract 509: DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers
Authors: Sujin Nam, Jiyoung Chae, Kyung-Ok Cho, Tae-Sung Koo, Jungho Kim, Myungeun Jung, Jeongmin Kim, Eunhee Kim
Journal: Cancer Research (2023)

Abstract Poly (ADP-ribose) polymerase 1 (PARP1) has been portrayed as a synthetic lethal target in cancers with homologous recombination deficiency. As all four PARP inhibitors on the market target both PARP1 and PARP2 isotypes, hematological toxicity issue emerged by PARP2 inhibition. To address the unmet need, we screened and optimized compounds exempt from the toxicity issue. Here, we present DM5167 as a new molecular entity with 0.41 nM of IC50 on the catalytic activity of PARP1. In addition, DM5167 exhibits an inhibitory profile against various PARP isotypes that differs from the four commercial PARP inhibitors. Specifically, DM5167 shows selectivity for PARP1 6.88 and 347.83 fold greater than PARP2 in the in vitro enzyme assay and DNA trapping assay, respectively. This contrasts with the corresponding PARP1/PARP2 selectivity values of 0.14 and 0.89 fold for olaparib, respectively. Moreover, DM5167 showed higher selectivity than AZD5305 in the enzymatic assay. The GLP toxicity studies assigned DM5167 as a safe compound based on its high NoAEL value, a general toxicity parameter. In addition, the safety margin of DM5167 was acceptable, indicating that DM5167 is a plausible drug candidate. To find suitable indications, we screened various human cancer cell lines using their inhibitory potentials against proliferation and colony formation. Several hits were seen in triple-negative breast cancer cell lines including MDA-MB-231, MDA-MB-436, MDA-MB-468 and HCC1395. In an orthotopic xenograft experiment in which MDA-MB-231 cells were implanted, oral administration of 50mpk of DM5167 inhibited tumor growth by 45.8%. In contrast, olaparib failed to reduce xenograft tumors derived from MDA-MB-231 cells. Collectively, these studies present DM5167 as an attractive anti-TNBC drug candidate. Citation Format: Sujin Nam, Jiyoung Chae, Kyung-Ok Cho, Tae-Sung Koo, Jungho Kim, Myungeun Jung, Jeongmin Kim, Eunhee Kim. DM5167, a novel selective PARP1 inhibitor, efficiently reduces growth of triple-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 509.
Abstract 2786: Targeting oncogene and inflammation for cancer therapy
Authors: Wei Wang, Sayantap Datta, Sadanandan E. Velu, Ming Luo, Ruiwen Zhang
Journal: Cancer Research (2023)

Abstract Accumulating evidence has demonstrated that the overexpression of and the loss of tumor suppressor genes contribute to the aggressiveness, poor prognosis, and poor response to treatment associated with advanced cancer. Overexpression and activation of the MDM2 and NFAT1 oncogenes frequently occur in human cancer and is associated with invasive and high grade/late-stage tumors, metastasis, and recurrence, and are negative prognostic factors for cancer patients. Dual targeting MDM2 and NFAT1 represents a novel molecular target for the treatment of cancer. However, most of the current MDM2 inhibitors have been designed to block the binding between MDM2 and p53, and have limited efficacy against tumors with mutant or deficient p53. Considering that high incidence of TP53 mutations and MDM2 overexpression in tumors, these MDM2 SMIs are expected to have low or no efficacy against those types of cancer. Therefore, there is an urgent need to identify a novel, p53-independent strategy to inhibit MDM2, in order to affirm the therapeutic value of targeting MDM2. In addition, as an important inflammatory factor, there are no specific NFAT1 inhibitors developed for cancer therapy. By employing crystallization screening, NMR-based screening, and high-throughput virtual and cell-based screening assays, we discovered a class of makaluvamine analogs with the desired property. One of these analogs, MA242, was identified as a potent and selective MDM2 and NFAT1 inhibitor. Its in vitro and in vivo anti-breast cancer activities and underlying mechanisms of action were evaluated in breast cancer cell lines with various p53 backgrounds. Our results demonstrated that MA242 directly bound to MDM2 and NFAT1 protein with high affinity and induced its protein degradation. As a result of this binding, MA242 decreased cell proliferation, and induced apoptosis and G2/M phase arrest in breast cancer cell lines, regardless of the p53 status. Furthermore, MA242 inhibited the tumor growth and metastasis in orthotopic and patient-derived xenograft (PDX) models, without any host toxicity. Single-cell sequencing results provided the molecular and cellular crosstalk between cancer and immune system, and identified the predictive biomarkers of response after the treatment. In conclusion, MA242 is a potent and selective MDM2 and NFAT1 dual inhibitor with distinct mechanisms of action compared to the existing inhibitors. Our data suggest that the dual targeting oncogene and inflammation is a promising strategy for the treatment of human cancer. (Supported by NIH R01CA214019 and a UH DDI Seed Grant.) Citation Format: Wei Wang, Sayantap Datta, Sadanandan E. Velu, Ming Luo, Ruiwen Zhang. Targeting oncogene and inflammation for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2786.